Interpretive Summary: Because of problems with the development of resistance to conventional pesticides, there is a critical need for new concepts and alternative approaches in controlling invertebrate pests such as insects and nematode worms. The basic premise of this research is that ‘FMRFamide’ neuropeptides (short chains of amino acids) serve as potent messengers in invertebrates such as nematode worms and insects to regulate vital functions. Nevertheless, these neuropeptides in and of themselves hold little promise as pest control agents because of susceptibility to being degraded in the target pest, and inability to pass through the outside skin and/or digestive tract. We must design neuropeptide mimics that resist degradation by enzymes in the digestive tract and blood of pest invertebrates and interact with the active site within an agricultural or medical pest in such a way as to either over-activate or block critical, neuropeptide-regulated life functions. We report on the isolation, identification and characterization of a new active site for the ‘FMRFamide’ class of invertebrate neuropeptides from the nematode labeled ‘C. elegans’, a prime model for parasitic nematode worms that plague man, livestock and crops. Key structural features of the neuropeptides have been identified that allow them to turn this active site on. This discovery will aid in the design of neuropeptide-like compounds capable of disrupting critical life functions in nematode worms. This work represents a spin-off of our primary focus on insect pests and brings us one step closer to the development of practical neuropeptide-like substances that will be effective in controlling invertebrate pests, including nematode worms and insects, in an environmentally friendly fashion.

Technical Abstract:
G-protein coupled receptors (GPCRs) are ancient molecules that sense environmental and physiological signals. Currently, the majority of the predicted Caenorhabditis elegans GPCRs are orphan. Here, we describe the characterization of such an orphan C. elegans GPCR, which is categorized in the tachykinin-like group of receptors. Since the C. elegans genome predicts only one tachykinin-like peptide (SFDRMGGTEFGLM), which could not activate the receptor, we hypothesized that one or some of the numerous FMRFamide related peptides (FaRPs) could be the cognate ligands for this receptor. This hypothesis was based on the suggestion that RFamides may be ancestral neuropeptides, from which a lot of the amidated neuropeptides, including tachykinins, derived. Indeed, we found that the orphan receptor encoded by the Y59H11AL.1 gene is activated by several C. elegans neuropeptides, including SPMERSAMVRFamide. These peptides activate the receptor in a concentration-dependent way.